Evaluation of Colorectal Cancer Inhibition Ability of Rosmarinus officinalis...

[Full title: Evaluation of Colorectal Cancer Inhibition Ability of Rosmarinus officinalis L. via Molecular Docking and Pharmacophore Analysis]

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OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2022.262.278 Research Article Evaluation of Colorectal Cancer Inhibition Ability of Rosmarinus officinalis L. via Molecular Docking and Pharmacophore Analysis 1 Thanh-Diem Nguyen, 2 Ly Le, 1 Tu-Binh Vo, 1 Kim-Lan Vo, 1 Hoang-Minh Le and 1 Huyen-Trang Vu 1 Faculty of Biotechnology, Nguyen Tat Thanh University, Hochiminh City 70000, Vietnam 2 Faculty of Biotechnology, International University, Vietnam National University, Hochiminh City 700000, Vietnam Abstract Background and Objective: Colorectal cancer is one of the most common cancers in the world. Mutated proteins of certain genes that control cell apoptosis have been identified as the cause of colorectal cancer. Natural compounds that interact and denature these proteins can be used to inhibit the activities of these proteins and help prevent tumour growth with limited side effects. However, searching for such new compounds through in vitro or in vivo tests is time-consuming and costly. Materials and Methods: In this study, 30 known compounds from the herbal plant Rosmarinus officinalis L. were used to study the inhibitory ability of certain types of colorectal cancer-causing proteins using the drug design simulation method. Due to the computer-based drug design simulation method, target disease-causing proteins can be simulated to interact with a variety of compounds from herbal medicinal plants to detect compounds with high affinity and low energy required for interaction. Following that, these potential compounds can be used for anti-cancer drug research. Results: Five compounds i.e., rosmarinic acid, carnosic acid, (E,E)-5,9,13-pentadecatrien-2-one,6,10,14-trimethyl, " -amorphene and " -bis-abolol had high affinity and strong interaction with target proteins which resulted in a high ability to denature and inactivate those unexpected proteins. The docking pharmacophore features were also analyzed for clarifying the affinity results. Conclusion: These potential compounds were proposed for further research on drugs for treating colorectal cancer. The drug design simulation method helps to shorten the time and cost significantly in the selection of drug compounds for testing on living cells and animals Key words: Rosmarinus officinalis, colorectal cancer, computer-aided drug design, molecular docking, pharmacophore, apoptosis, S. allylcysteine Citation: Nguyen, T.D., L. Le, T.B. Vo, K.L. Vo and H.M. Le et al. 2022. Evaluation of colorectal cancer inhibition ability of Rosmarinus officinalis L. via molecular docking and pharmacophore analysis. Int. J. Pharmacol., 18: 262-278 Corresponding Author: Huyen-Trang Vu, Faculty of Biotechnology, Nguyen Tat Thanh University, Hochiminh City 70000, Vietnam Copyright: © 2021 Thanh-Diem Nguyen et al. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

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Int. J. Pharmacol., 18 (2): 262-278, 2022 INTRODUCTION Colorectal Cancer (CRC) is a tumour that develops in the colon, rectum, or appendix. This is the third most common cancer, the second common cause of death in Western countries 1 . The incidence of CRC is on the rise worldwide, especially in developing countries 2 . In Vietnam, CRC is ranked as the fifth group of cancer with the number of new cases causing death at a rate of 4.1% among all types of cancers (https://gco.iarc.fr/). Like other types of cancer, CRC is caused by the changes in the genetic system that leads to uncontrol of cell division. The deletion mutation of gene loci related to tumour suppressor genes in the chromosome was reported to relate to the development of CRC in some previous studies, especially genes relating to cell proliferation and apoptosis such as BRAF , TP 53 , KRAS and ALK 3-6 . The BRAF gene is a proto-oncogene belonging to the Serine/Threonine Kinase family. BRAF protein expressed somatic mutations in a variety of tumours, primarily malignancies 1 . The mutated β -catenin gene increased cell proliferation and inhibits apoptosis. This gene mutation accounts for up to 10% of all CRC cases 7 . The TP 53 gene encodes a protein that aids in the cell cycle and apoptosis 8 . The TP 53 gene mutation was found in more than 50% of cases of CRC, this is considered a marker in the development of tumours to cancer 9 . The KRAS gene encoding the Ras protein is responsible for the control of cell growth, differentiation and apoptosis. Some human cancers have been shown to relate to the expression of mutated Ras protein (oncogenic Ras ). The appearance of mutant Ras proteins accounts for 15-20% in malignant tumours 10 and mutation of the KRAS gene accounts for 25-60% of cases of CRC 11 . The genetic information of protein Anaplastic Lymphoma Kinase (ALK) which is involved in cell growth is from the gene ALK . Mutations (changed mutation) of the ALK gene and protein have been found in several types of cancer, including neuroblastoma and lung cancer. The appearance of the mutant ALK protein increased the growth of cancer cells 12 . These genes encode proteins that control cell proliferation and apoptosis and in turn, mutated proteins cause uncontrolled cell proliferation leading to tumour creation. The inactivation of these mutant proteins will help prevent the growth of tumours 13 The common cancer treatments include chemotherapy and radiotherapy. However, these methods often adversely affect the health of patients. Therefore, many studies have suggested the use of natural compounds in tumour suppression. These compounds can interact with mutated proteins that cause cancer, leading to the inhibition of tumour growth but little damage to the human body. Some compounds extracted from aged garlic ( Allium sativum ), especially S-allylcysteine and S-allylmercapto-L-cysteine have been shown to prevent the growth of certain types of cancer 14,15 . The flavonoids from papaya seeds also showed positive results when treated on some cancer cell lines in mice 16 . Rosemary ( Rosmarinus officinalis L.) is a popular plant in Vietnam that is often used for ornamental purposes, spice in cooking, or for repelling insects. In 2016, this plant was also proved to inhibit CRC cells in mice 17 by the two compounds rosmarinic acid and carnosic acid through in vitro test However, there are still many other compounds of rosemary which are abundant and have not been put into research. Rosemary essential oil accounts for 27% of the plant, contains camphor (5.0-21%), 1.8-cineole (15-55%), " -pinene (9.0-26%), borneol (1.5-5.0%), camphene (2.5-12%), $ -pinene (2.0-9.0%), limonene (1.5-5.0%) 18 and other bioactive substances such as rosmarinic acid (8%), carnosic acid (30%), carnosol (17%) and ursolic acid (6%) 19 , which and can be extracted from different organs i.e., the leaves, stems and flower stalks. Even so, searching for potential anti-cancer compounds through in vitro and in vivo tests is extremely timeconsuming and costly 14-17 . With the development of computer science, simulation approaches have been effectively applied in many areas of life, including medical science, which can overcome those mentioned problems. The Structure-Based Drug Design (SBDD) method allows the batch simulation of docking between many plant compounds and disease-causing molecules just in hours 20 . The docking pharmacophores with higher affinity, i.e., lower binding energy required, are potential results for protein denaturation leading to inactivation of the target molecules. From initial docking results, potential compounds can be used to perform further wet experiments which require significantly less time and cost. This Computer-Aided Drug Design (CADD) method, which is a combination of computer science, chemistry, biology has been proven to be important for the development of new drugs from herbal plants. In this study, we simulated the binding affinity between compounds of rosemary and some mutated proteins causing a colorectal tumour The study aims to propose potential compounds for inhibiting tumours of CRC, serving for further steps of drug treatment on this dangerous disease MATERIALS AND METHODS Study area: The study was carried out at the Department of Biotechnology, Nguyen Tat Thanh University, Vietnam from July, 2020-June, 2021) Ligands and proteins preparation: Thirty compounds of rosemary used as ligands in this study (Table 1) were 263

[Find the meaning and references behind the names: Dalton, Alpha]

Int. J. Pharmacol., 18 (2): 262-278, 2022 Table 1: Information and 2-D structure downloaded from the ZINC database of thirty studied ligand compounds of the rosemary plant Molecular weight Number Zinc Name Structure (dalton) xlogP 1 ZINC 00899870 Rosmarinic acid 359.31 1.63 2 ZINC 03984016 Carnosic acid 331.432 4.6 3 ZINC 12358879 (E,E)-5,9,13- Pentadecatrien 262.437 6 -2-one, 6 10, 14-trimethyl 4 ZINC 01849759 " -bis-Abolol 222.372 4.68 5 ZINC 02083320 Caryophyllene oxide 220.356 4.14 6 ZINC 01677809 Linalyl propionate 210.317 4.28 7 ZINC 57988166 Copaene 204.357 5.75 8 ZINC 08234282 Caryophyllene 204.357 5.17 9 ZINC 30726967 Alpha-caryophyllene 204.357 5.31 264 Me Me Me Me Me O H C 2 Me Me Me Et O O Me H Me Me Me H H Me Me Me H H CH 2 Me Me Me Me H Ma O H H Ch 2 Ma Ma HO HO OH OH O O OOO G Me OH HO Me Me Me G OOC H Ma Ma Ma Ma HO

Int. J. Pharmacol., 18 (2): 262-278, 2022 Table 1: Continue Molecular weight Number Zinc Name Structure (dalton) xlogP 10 ZINC 70455185 " -Amorphene 204.357 5.97 11 ZINC 00388664 L-Bornyl acetate 196.29 3.05 12 ZINC 00899536 5-Methyl-2-(1-methylethyl)-phenol, acetate 192.258 2.91 13 ZINC 00001411 o-Methyl eugenol 164.204 2.1 14 ZINC 02510141 di-n-Butylethylamine 158.309 3.59 15 ZINC 30724426 Sabinene hydrate 154.253 2.32 16 ZINC 00967566 Eucalyptol 154.253 2.72 17 ZINC 00968131 4-Thujanol 154.253 2.32 18 ZINC 01529819 " -Linalool 154.253 3.21 265 Me Me Me Me O O H Me Me Me Me O O Et Et Et HN + OH H Me Me Me Me Me Me O Me Me Me OH H Me Me Me CH 2 OH H C 2 OH O e M Me Me Me Me H H

[Find the meaning and references behind the names: Carene]

Int. J. Pharmacol., 18 (2): 262-278, 2022 Table 1: Continue Molecular weight Number Zinc Name Structure (dalton) xlogP 19 ZINC 00967533 L-Borneol 154.253 2.35 20 ZINC 03861537 Terpinen-4-ol 154.253 2.6 21 ZINC 02034811 3-Pinanone 152.237 2.39 22 ZINC 14588455 Carvone 150.221 2.51 23 ZINC 00967600 Verbenone 150.221 2.44 24 ZINC 33845547 (Z)-Cinerone 150.221 2.06 25 ZINC 18157343 Piperitenone 150.221 2.51 26 ZINC 00967562 3-Carene 136.238 3.45 27 ZINC 00968230 Camphene 136.238 3.33 266 Me Me Me H H O Me Me O CH 2 H H O Me Me Me Me Me O Me Me O CH 2 Me H Me Me H Me Me Me OH H Me Me Me HO H H C 2 Me Me H

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Int. J. Pharmacol., 18 (2): 262-278, 2022 Table 1: Continue Molecular weight Number Zinc Name Structure (dalton) xlogP 28 ZINC 59586951 2-Carene 136.238 3.45 29 ZINC 02003408 oct-7-en-4-ol 128.215 2.53 30 ZINC 00901249 3,4-Dimethoxy styrene 120.151 1.74 referenced from many published sources 18,19,21 . Molecular information of ligand was downloaded from ZINC database (http://zinc.docking.org/) including chemical structure, xlogP, aromatic rings, number of rotation bonds and was then saved as A Tripos Mol 2 format. All the amide bonds of each ligand were made to not rotate using AutoDockTools 1.5.6 software 22 The data was then turned into PDBQT (Protein Data Bank (PDB), Partial Charge (Q) and Atom Type (T)) format, which is a supported format for running on the AutoDock 4.0 software and increasing the storage capacity of atomic coordinates, partial charge, atomic types of docking molecules in comparison with previous format (http://autodock. scripps. edu/) Six mutated proteins involved in causing CRC including a mutated form of each four proteins $ -catenin (PDB molecular ID i.e., 1 JPW), TP 53 (4 IBW), KRAS (4 TQ 9), ALK (5 FTO) and two mutated forms of BRAF protein (5 HID and 4 R 5 Y) 23-28 were considered as receptors for docking in this study (Table 2). Other molecular information and 3 D structure of these proteins were also recorded from PDB (http://www.rcsb.org/) including resolutions, chains, existed ligands and determination methods. Each protein was prepared using AutoDockTools software 1.5.6 to achieve optimal simulation through 4 steps: (1) Adding polarized hydrogens, (2) Fusing non-polar hydrogens, (3) Removing water molecules and (4) Creating grid boxes. Adding polarized hydrogen bonds is important for docking since hydrogen bonds play a major role in stabilizing protein-ligand complexes 29 . As water molecules do not join the docking, the removal of water molecules from proteins makes computational accounts easier and avoids interference in searching for ligand molecules, which can create more favourable contact with protein receptors 30 . Grid boxes were established for verifying docking regions on 6 target proteins with 30×30×30 dimensions and default spacing at 1.000 Å (Table 3). Creating a grid box helps the program to determine the appropriate binding space between protein and ligand, thereby providing optimal binding results 31 . The data was then saved in PDBQT format for docking in the next step Molecular docking and pharmacophore analysis: One ligand was docked with one receptor in the space of one grid box for each running. The rigid docking simulation between a target protein and ligand was first performed using the AutoDock Vina program 32 . Result data of docking was converted into PDB (Protein Data Bank) format using OpenBabel program 33 and was visualized by BIOVIA Discovery Studio Visualizer software 34 . Pharmacophore features of the simulation were analyzed based on the affinity and molecular interactions. For further analyses, flexible docking was next conducted. In the flexible docking, besides one protein receptor and one ligand, a flexible amino acid inside the receptor was required as a flexible factor to be included in the running setup 35 . The amino acids that are tightly bound to ligand from the result of rigid docking were chosen for this flexible docking step Pharmacophore features of flexible docking were analyzed in comparison with the previous rigid pharmacophore 267 Me H Me Me H CH 2 OH Et O

[Find the meaning and references behind the names: Peg, Size, Full, Ion, General, Good]

Int. J. Pharmacol., 18 (2): 262-278, 2022 Table 2: Information obtained from the PDB database of six mutated proteins involved in causing CRC in the study PDB accession Resolution Chains Existed ligands Structure 1 JPW 2.5 Å A, B, C - 4 IBW 1.791 Å A, B A: Zn ion A, B: 1,2-Ethanediol 4 R 5 Y 3.5 Å A, B A, B: C 25 H 17 F 3 N 4 O 3 4 TQ 9 1.491 Å A, B A, B: GDP, Mg ion 5 HID 2.5 Å A, B A, B: B 1 E, PEG 5 FTO 2.22 Å A A: YMX Table 3: Coordinate and dimension information of 10 grid boxes established for verifying docking regions on 6 target proteins in the study Protein accession Grid box Center x Center y Center z Size ( Å ) 5 HID GRID 1 3.056 -13.417 -9.417 30×30×30 GRID 2-full 3.917 -1.667 -11.861 30×30×30 1 JPW GRID 1-full 153.194 -1.861 6.528 30×30×30 4 IBW GRID 1 -26.139 -7.5 -23.889 30×30×30 GRID 2 -23.859 1.53 -15.86 30×30×30 4 R 5 Y GRID 1 19.776 13.364 -15.307 30×30×30 GRID 2-full 17.361 0.444 -1.361 74×12×18 4 TQ 9 GRID 1 0.417 -10.028 37.889 30×30×30 GRID 2-full -5.502 -22.603 26.972 42×36×14 5 FTO GRID 1 6.676 19.601 8.223 30×30×30 RESULTS Rigid docking results: The rigid docking results of 30 ligands with 6 target proteins at different grid boxes, respectively were shown in detail in Table 4. In general, rosmarinic acid and carnosic acid showed good binding results with all six examined proteins. Rosmarinic acid gave the highest affinity with 4 TQ 9 protein at the lowest binding 268

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Int. J. Pharmacol., 18 (2): 262-278, 2022 Fig. 1: Free binding energy between 30 ligands of Rosemary plant and 6 CRC carcinogenic proteins by Rigid docking simulation The lower the free binding energy was required, the higher the binding affinity was energy -10.4 kcal mol G 1 and with the remaining proteins at around -9.7 and -8.8 kcal mol G 1 (Fig. 1). The following was carnosic acid which had the highest affinity for binding to 5 FTO protein at -9.5 kcal mol G 1 and to other proteins at a range from -9.4 and -8.9 kcal mol G 1 . Besides rosmarinic acid and carnosic acid, four other compounds i.e., (E, E)-5,9,13- pentadecatrien-2-one,6,10,14-trimethyl; " -caryophyllene, " - amorphene and " -bis-abolol which had the binding energy lower than -8.0 kcal mol G 1 with some of the mutated protein were also used for further flexible docking and pharmacophore analyzing Flexible docking and pharmacophore analysis: The absolute values of free binding energy referred from flexible docking were all better than that of rigid docking (Fig. 2). The differences ranged from 0.1 up to 1.7 kcal mol G 1 The details were presented in Table 5. Rosmarinic acid gave the best affinity result with 4 TQ 9 at G 11.1 kcal mol G 1 instead of -10.4 kcal mol G 1 from rigid docking (Fig. 2). The following was a complex of carnosic acid and 1 JPW at -10.7 kcal mol G 1 , which was better than rigid docking by a distance of 1.7 kcal mol G 1 . Flexible docking of other three ligands " -abolol, " -amorphene and (E, E)-5,9,13- pentadecatrien-2-one,6,10,14-trimethyl also created a favourable affinity with 4 R 5 Y, 5 FTO and 4 R 5 Y respectively at -10.0, -9.9 and -9.4 kcal mol G 1 , corresponding. Though the docking result was better, the flexible binding energy of " -caryophyllene with both of target proteins 5 FTO and 4 R 5 Y 269 0 -2 -4 -6 -8 -10 -12 Free bi ndi ng en erg y (k cal mol −1 ) -9.0 -9.5 -10.4 -9.8 -8.8 (E,E)-5 ,9 ,13 -Pent ad ecat ri en -2 on e, 6, 10 ,14 -t rimethy l (Z) -Ciner one 2-Car ene 3, 4- D ime th oxy st yre ne 3-Car ene 3-P ina no ne 4- Thu janol 5- Meth yl -2 -(1 -met hyl ethy l) -ph eno l, acet ate α-caryop hyl le ne Camp he ne Carno si c acid Carvon e Caryop hy ll en e oxid e Caryop hy ll en e C op aen e di -n -But yl et hyl ami ne Eu calyp tol L-Bo rn eol L -Bor ny l ace ta te Li na ly i p ropi on at e oc t-7 -en -4 -ol o- Meth yl eu ge no l Pip eri te no ne Ros m ar in ic ac id Sab ine ne hydr ate Te rp in en -4 -o l Ver be no ne α- Am or phe ne α-b is -A bol ol α-Li na lool 5 HID 1 JPW 4 IBW 4 R 5 Y 4 TQ 9 5 FTO

[Find the meaning and references behind the names: Present, Bond]

Int. J. Pharmacol., 18 (2): 262-278, 2022 Fig. 2: Best free-binding energy of 6 potential ligands with target proteins based on flexible docking and rigid docking were still not reached -9.0 kcal mol G 1 , this compound was not included in the following analysis. The pharmacophore of some high binding complexes was analyzed for more clarity of the binding mechanism. In comparison with rigid docking (Fig. 3 a), flexible docking of rosmarinic acid with 4 TQ 9 produced 3 additional van der Waals bonds and 1 attractive charge (Fig. 3 b). Thus, even though less than 1 Pi-cation and an additional unfavourable bump were present, the interaction affinity of this flexible complex was still better by about 0.7 kcal mol G 1 . In the complex between carnosic acid and 1 JPW (Fig. 3 c-d), despite the reduction of 1 van der Waals bond and the appearance of two more unfavourable bumps in flexible docking, there was an increased range of molecular bonds including 2 Hydrogen bonds, 1 Akyl bond, 1 Pi-Alkyl bond and 1 charge bond (Fig. 3 d), resulting in a significant increase of the interaction affinity (from -9.0 and -10.7 kcal mol G 1 ). This showed that flexible docking creates more sites of interaction between ligand and protein than rigid docking The same happened when comparing rigid and flexible pharmacophore in the complexes of 5 FTO with " -amorphene (Fig. 3 e-f) and 4 R 5 Y with (E,E)-5.9,13-pentadecatrien-2-one, 270 (E,E)-5, 9, 13-pentadecatrien- 2 one, 6, 10, 14-trimethyl Proteins Ligands 5 HID 5 FTO 4 R 5 Y 5 HID 5 FTO 4 R 5 Y 5 FTO 4 R 5 Y 5 FTO 4 R 5 Y 5 HID 5 FTO 4 TQ 9 4 R 5 Y 4 IBW 1 JPW 5 HID 5 FTO 4 TQ 9 4 R 5 Y 4 IBW 1 JPW Carnosic acid Rosmarinic acid a -bis-abolol a -amorphene a -caryophyllene -12 -10 -8 -6 -4 -2 0 Free binding energy of docking (kcal mol ) −1 -10 -8.8 -9.9 -9.8 -9.4 -8.9 -11.1 -10.4 -10.7 -9.0 Flexible docking Rigid docking

[Find the meaning and references behind the names: Ener, Bold, Able]

Int. J. Pharmacol., 18 (2): 262-278, 2022 271 T able 4: Free-binding ener gy (kcal mol‾ ) between 30 ligands of rosemary plant and 6 C R C carcinogenic proteins by rigid docking si mulation 1 Ligands -7.9 -7.6 -6.7 -6.3 -6.1 -8.9 -6.5 -7.8 -7.7 -9 -6.6 -6.6 -5.8 -5.1 -5.1 -6.7 -5.2 -6.4 -6 -7 -6 -6 -5.4 -4.5 -4.7 -6.1 -5 -5 -5.7 -5.9 -5.4 -5.5 -5 -4.4 -4.6 -5.8 -4.9 -5.4 -5 -6 -6.2 -6.3 -5.2 -4.7 -4.6 -6.2 -5.3 -5.6 -5.7 -6.5 -5.9 -5.9 -5.7 -4.6 -4.7 -5.9 -5.4 -5.2 -6.2 -5.9 -6.1 -6 -5.8 -4.6 -4.7 -6 -5.4 -6 -5.6 -6.8 -6.9 -6.7 -6.3 -5.3 -5.7 -6.9 -6.1 -6.4 -6.7 -7.6 -7.7 -7.6 -6.9 -5.3 -5.3 -8.2 -6.7 -7.1 -7.2 -8.4 -5.6 -5.6 -5.1 -4.4 -4.4 -6 -4.8 -4.7 -5.5 -5.2 -9.3 -9.1 -9 -7 -8.2 -8.9 -8.8 -8.1 -9.4 -9.5 -6.9 -6.9 -5.7 -5 -5 -7 -5.6 -6.1 -5.9 -7 -7.1 -7.1 -7.2 -5.4 -5.4 -7.5 -6.5 -6.2 -6.9 -7.8 -7.3 -7.2 -6.7 -5.4 -5.5 -7.3 -6.5 -6.2 -7.2 -7.3 -7.3 -7.3 -7 -5.4 -6.2 -7.2 -5.9 -6.9 -7 -7.5 -5.9 -5.9 -4.8 -4.6 -4.7 -5.8 -4.8 -5.2 -5.3 -5.7 -5.7 -5.7 -5.3 -4.5 -4.5 -5.6 -5.4 -4.8 -5.6 -5.5 -5.8 -5.8 -5.9 -4.4 -4.9 -5.4 -5.2 -5.1 -5.5 -5.6 -6.5 -6.5 -6.3 -5.1 -5.4 -6.4 -5.9 -6.2 -6.9 -6.3 -6.5 -6.5 -6.3 -5.1 -5.4 -6.4 -5.9 -6.2 -6.9 -6.3 -5.6 -5.7 -4.8 -4.5 -4.7 -5.7 -4.4 -4.9 -5.1 -5.5 -7 -7 -5.8 -5.1 -5.3 -7 -5.6 -7.2 -6.2 -7.4 -6.6 -6.6 -5.4 -5.4 -5.5 -6.7 -5.7 -5.9 -5.8 -6.8 -9.7 -8.3 -9.2 -7.7 -9.3 -9.4 -8.9 -8.8 -10.4 -9.7 -5.8 -5.7 -5.6 -4.7 -4.8 -6 -5.4 -5.3 -5.9 -5.8 -6.3 -6.2 -5.8 -4.7 -4.9 -6.2 -5.6 -5.6 -5.9 -6.3 -6.2 -6.2 -5.8 -4.9 -5 -6.2 -5.4 -5.5 -6.1 -5.7 -8.3 -8.3 -7.2 -5.8 -5.7 -8.4 -6.6 -7.2 -7.4 -9.8 -8.2 -8.3 -6.9 -5.6 -5.8 -8.8 -6.6 -7.5 -7.1 -8 -6.3 -6.3 -5.6 -4.9 -5 -6.4 -5.5 -5.6 -5.9 -6.5 Protein accession Grid box GRID 1 G R ID 2 full G R ID 1 full GRID 1 GRID 2 GRID 1 G R ID 2-full GRID 1 G R ID 2-full GRID 1 1 JPW 5 H ID 4 IBW 4 R 5 Y 4 T Q 9 5 F TO Bold cell: Free-binding ener gy that is lower than -8 kcal mol - 1 (E,E)- 5, 9, 13-Pentadecatrien-2-one, 6, 10, 14-trimethyl (Z)-Cinerone 2-Carene 3,4-Dimethoxy styrene 3-Carene 3-Pinanone 4-Thujanol 5-Methyl-2-(1-methylethyl)-phenol, acetate alpha-caryophyllene Camphene Carnosic acid Carvone Caryophyllene oxide Caryophyllene Copaene di-n-Butylethylamine Eucalyptol L-Borneol L-Bornyl acetate Linalyl propionate oct-7-en-4-ol o-Methyl eugenol Piperitenone Rosmarinic acid Sabinene hydrate Terpinen-4-ol V erbenone α–Amorphene α–bis-Abolol α–Linalool

[Find the meaning and references behind the names: Frame, Bridge, Salt, Black]

Int. J. Pharmacol., 18 (2): 262-278, 2022 Fig. 3 (a-j): Pharmacophore features the highest affinity complexes of 5 potential compounds with target proteins, (a, b): Complex of 4 TQ 9-Rosmarinic acid, (c, d): Complex of 1 JPW and Carnosic acid, (e ,f): Complex of 5 FTO and ( " ) Amorphene, (g, h): Complex of 4 R 5 Y and (E,E)-5,9,13-pentadecatrien-2-one,6,10,14-trimethyl, (i, j): Complex of 5 HID and a-bis-Abolol (a, c, e, g, i): Pharmacophores from rigid docking, ( b, d, f, h, j): Pharmacophores from flexible docking. The hydrocarbon structure of the ligand was shown in a black frame. The global shape was the amino acid of the receptor that has interactions with the ligand. Different interactions of complex were represented in different corresponding colours) 272 (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) Pi-Alkyl Alkyl Conventional hydrogen bond Salt bridge Pi-sigma Attractive charge Pi-Cation Van der Wasls Unfavourable Bump

[Find the meaning and references behind the names: Gln, Thr, Ile, Val, Leu, Asn, Ser, Lys, Arg, Aci, Pote, Asp]

Int. J. Pharmacol., 18 (2): 262-278, 2022 273 Table 5: Free-binding energy between flexible docking of 6 pote ntial ligands with CRC carcinogen receptors using different fle xible amino acids in comparison with rigid docking Free-binding energy of docking --------------------------------------------------------------- --------------------------------------------------------------- --------------------------------------------------------------- ----------- Ligand Protein Grid box Flexible docking using different amino aci ds Minimum Rigid docking Carnosic acid 1 JPW 1 JPW arg 661 b asn 362 c leu 286 c thr 289 c thr 330 c tyr 331 c arg 582 b gln 322 c -8.9 -9.1 -9 -9.4 -9 -10.7 -8.5 -9.4 -10.7 -9 4 IBW 4 IBW asn 268 a leu 111 a ser 269 a thr 102 a -8.8 -8.2 -8.3 -8.3 -8 -8.8 4 R 5 YA ile 527 a ile 572 a leu 505 a leu 514 a thr 529 a val 504 a -9.1 -9 -10.1 -9.7 -8.9 -9.2 -10.1 -8.9 4 R 5 YA 4 R 5 Y full asp 555 b thr 589 b val 511 b -8.8 -8.8 -8.8 -8.8 4 TQ 9 4 TQ 9 full arg 161 b asp 154 a ile 142 a thr 158 a thr 127 a tyr 157 b -9.9 -9.4 -9.5 -9.5 -9.7 -9.2 -9.4 -9.9 5 FTO 5 FTO leu 1196 a leu 1256 a met 1199 a phe 1127 a val 1130 a val 1180 a -10.3 -9 .5 -10.3 -10 -9.6 -9.8 -9.5 -9.5 5 HID 5 HID ile 463 a leu 514 a phe 583 a phe 595 a thr 529 a trp 531 a val 471 a -10.4 -9.3 -10.3 -9.5 -9.5 -10.4 -9.3 -9.4 -9.4 5 HID full ile 463 a phe 583 a phe 595 a thr 529 a trp 531 a val 471 a -9.1 -10.4 -9.5 -9.6 -9.1 -9.2 -9.3 Rosmarinic acid 1 JPW 1 JPW arg 587 b asp 249 c his 524 b lys 288 c thr 289 c val 58 4 b -9.5 -9.2 -9.5 -9.3 -9.2 -9.4 -9.2 -9 4 IBW 4 IBW arg 282 a gln 144 a his 115 a phe 113 a ser 116 a trp 146 a -9.7 -9.3 -9.5 -9.4 -8.9 -9.3 -9.3 -9.7 4 R 5 Y 4 R 5 YA ile 527 a leu 505 a leu 514 a thr 529 a val 504 a -9.8 -9.4 -9.8 -9.2 -9.8 -9.4 -9.8 4 R 5 Yfull arg 562 a val 511 a -8.9 -9.3 -9.1 4 TQ 9 4 TQ 9 full arg 161 b asp 154 a gln 131 a ile 142 a arg 135 a -11.1 -10.4 -11.1 -10.6 -10.1 -10.5 -10.6 5 FTO 5 FTO leu 1256 a phe 1127 a val 1130 a -9.8 -9.7 -9.8 -9.8 -9.8 5 HID 5 HID ile 463 a leu 514 a phe 595 a thr 529 a val 471 a -10.4 -9.7 -10.1 -9.8 -10.4 -9.6 -9.8 5 HIDfull ile 463 a leu 514 a phe 595 a thr 529 a val 471 a -8.3 -8.1 -8.7 -8.4 -8.4 -8.2 (E,E)- 5, 9, 4 R 5 Y 4 R 5 YA leu 505 a leu 514 a thr 529 a val 471 a val 504 a lys 483 a -9.4 -8.9 13-Pentadecatrien -9.4 -8.9 -8.9 -8.9 -8.8 -9.1 -2-one, 6, 10, 5 FTO 5 FTO leu 1122 a leu 1256 a phe 1127 a val 1130 a -9.3 -9 14-trimethyl -9.3 -9.3 -9.3 -9.1

Int. J. Pharmacol., 18 (2): 262-278, 2022 274 Table 5: Continue Free-binding energy of docking --------------------------------------------------------------- --------------------------------------------------------------- --------------------------------------------------------------- --------------------------- Ligand Protein Grid box Flexible docking using different amino aci ds Minimum Rigid docking " -Caryophyllene 4 R 5 Y 4 R 5 YA ile 463 a leu 514 a phe 583 a phe 595 a thr 529 a trp 53 1 a val 471 a -8.5 -8.2 -8.2 -8.2 -8.4 -8.5 -8.2 -8.3 -8.3 5 FTO 5 FTO leu 1122 a leu 1196 a leu 1256 a phe 1127 a val 1130 a -8.8 -8.4 -8.8 -8.5 -8.5 -8.5 -8.6 " -Amorphene 4 R 5 Y 4 R 5 YA ile 463 a leu 514 a phe 583 a phe 595 a thr 529 a trp 531 a v al 471 a -8.7 -8.4 -8.6 -8.3 -8.7 -8.4 -8.4 -8.6 -8.4 5 FTO 5 FTO leu 1122 a leu 1196 a leu 1256 a phe 1127 a val 1130 a lys 1150 a -9.9 -9 8 -9.9 -9.9 -9.8 -9.9 -9.9 -9.7 5 HID 5 HID ile 463 a leu 514 a leu 597 a phe 583 a phe 595 a thr 529 a trp 531 a val 471 a -8.7 -8.3 -8.6 -8.5 -8.4 -8.7 -8.5 -8.3 -8.5 -8.4 5 HID full ile 463 a leu 514 a phe 583 a phe 595 a trp 531 a thr 529 a val 471 a -8.3 -8.6 -8.5 -8.7 -8.5 -8.3 -8.3 -8.4 " -bis-Abolol 4 R 5 Y 4 R 5 YA ile 463 a ile 572 a leu 505 a phe 583 a phe 595 a thr 529 a trp 531 a val 471 a leu 514 a lys 483 a -10 -8.8 -8.8 -8.8 -8.7 -8.8 -8.9 -8.7 -9.1 -8.9 -10 -8.9 5 FTO 5 FTO leu 1122 a leu 1196 a leu 1256 a phe 1127 a val 1130 a val 1180 a -8.3 -8 -8.1 -8 -8.3 -8.2 -8 -8 5 HID 5 HID ile 527 a leu 505 a leu 514 a phe 583 a thr 529 a trp 531 a val 471 a phe 595 a cys 532 a -9.3 -8.2 -8.2 -8.5 -9.3 -8.5 -8.3 -8.4 -8.8 -8.1 -8.2 5 HID full ile 527 a leu 505 a leu 514 a phe 583 a thr 529 a trp 531 a val 471 a -8.3 -8.2 -8.4 -9.3 -8.5 -8.3 -8.4 -8.8 Table 6: Molecular interactions of the highest affinity complex es from rigid docking and flexible docking Docking Van der Convetional hydrogen Salt Attractive Unfavorable Complex type waals bond bridge Alkyl Pi-Alkyl charge Pi-cation Pi-sigma bump Total 4 TQ 9-Rosmarinic acid Rigid 1 4 0 0 2 1 1 0 0 9 Flexible 3 4 0 0 2 2 0 0 15 12 1 JPW-Carnosic acid Rigid 5 1 1 2 0 0 0 0 0 9 Flexible 4 3 0 3 1 1 0 0 2 14 5 FTO- Rigid 0 0 0 9 6 0 0 0 0 15 " -Amorphene Flexible 0 0 0 10 6 0 0 0 0 16 4 R 5 Y-(E,E)5,9,13- Rigid 1 0 0 5 0 0 0 0 0 6 Pentadecatrien-2-one Flexible 1 0 0 6 0 0 0 0 0 7 6,10,14-trimethyl 5 HID- Rigid 1 0 0 6 5 0 0 1 0 13 " -bis-Abolol Flexible 1 1 0 7 2 0 0 0 3 14

[Find the meaning and references behind the names: Jessy, Change, Force, Quite, Barni, Bind, Clash, Show, Works, Moore, Cardinal, Large, Might, Part, Coo, Caco, Hrs, Get, Cox, Lovo, Plays, Reason, Link, Case, Rich, Weeks, Line, Cloud]

Int. J. Pharmacol., 18 (2): 262-278, 2022 6,10,14-trimethyl (Fig. 3 g-h), although only 1 alkyl bond was improved and the free bond energy difference was not very high. However, this result still recommended the importance of some molecular bonds in the interaction affinities. For the interaction between 5 HID and " -bis-abolol, the energy difference was quite different (from -8.2 and -9.3 kcal mol G 1 ) due to the increase of 1 Alkyl bond and 1 Hydrogen bond (Fig. 3 i-j). The statistics of intermolecular interactions were detailed in Table 6. DISCUSSION The two compounds i.e., carnosic acid and rosmarinic acid showed the best binding with all studied colorectal carcinogenic proteins. Previously, carnosic acid was also tested on CRC Caco-2, HT 29 and LoVo cell lines by Barni et al 36 . The study found out that this compound had strong inhibition of the tumour growing by inactivating both the carcinogenic mRNA, which encodes the COX-2 cancer-causing pathway and its protein. In 2016, rosmarinic acid and carnosic acid were also proven to have an anti-cancer effect on some colorectal cancer cell lines by Jessy Moore et al 17 . However, it took 24 hrs to test in vitro inhibitory ability of these compounds on each cell line. As for in vivo test, the treatment effect on mice was evaluated after 11, 16 weeks using carnosic acid and rosmarinic acid, respectively. For our in silico study, it took only hours to get the docking result and select the best ligands. Although it is necessary to further perform in vitro or in vivo tests for drug development, the computer works significantly reduce cost and time-consuming as the first step for selecting potential subjects from a large number of new compounds of herbal plants 37 . Besides, our study was completely consistent with the studies of Moore 17 and Barni 36 , which not only reconfirmed the role of these two compounds in inhibition of colorectal cancer but also convincingly demonstrated the reliability of this simulation method for other Computer-Aided Drug Design studies. The change in interaction energy of flexible docking compared with rigid docking in the complex between rosmarinic acid and 4 TQ 9 occurred due to the addition of 2 van der Waals bonds and 1 attractive charge bond and the appearance of an unfavourable bump. Van der Waals is an attractive force due to dipole-induced interactions, which is weak in comparison with chemical bonds 38 . Besides, the existence of unfavourable pumps, which is known as unexpected intermolecular steric clash, have been proved to show unstable interactions and binding between interacting amino acids and drug atoms 39 as well. Hence the significant increase of binding capacity, in this case, might be due to the appearance of the attractive charge, which in turn is caused by the existence of the -COO - group in the structure of rosmarinic acid (Fig. 3 b). The carboxylic acid functional group plays a cardinal role in the biochemistry of living systems as well as in drug design. Since endogenous substances, such as amino acids, triglycerides and prostanoids, possess the carboxylic acid moiety. The acidity as well as the ability to establish relatively strong electrostatic interactions and hydrogen bonds is the reason why this functional group is often part of drug-target interactions 40 and pharmacophore of diverse classes of therapeutic agents 41 . The two compounds rosmarinic acid and carnosic acid, which gave the best binding results in both rigid and flexible docking on this study, all contain this -COO G group Furthermore, these two ligands also contained aromatic rings in their structure. Rosmarinic acid had two phenol rings, the greatest number of phenol rings in comparison with other compounds in the study. Polyphenol components have been identified for their ability to prevent various types of cancer, in both experimental and simulated research 42,43 . These compounds had the potential to change the primary and secondary structures due to methyl, glycosyl and hydroxylation processes 44,45 , which make it easy to link with amino acids to increase the binding capacity between ligands and receptor proteins. The interactions of Pi-cation and Pi-alkyl were all created due to the existence of a pi-electron cloud over these aromatic groups. Pi-alkyl is the interaction of the aromatic group and electron group of an alkyl group A large number of pi-sigma (pi-alkyl and pi-cation) interactions were mainly involved in charge transfer, which helps to transfer drugs between receptor binding sites 38 . Meanwhile, Pi-cation interaction is the binding force between the cations and the pi surface (the face of an electron-rich pi system) of the aromatic structure through a non-covalent force. Pi-cation was important in many proteins that bind ligands or cation substrates 46 Three other potential compounds i.e., " -amorphene and " -bis-abolol and (E,E)-5,9,13-pentadecatrien-2-one,6,10,14- trimethyl mainly consisted of methyl groups (-Me) when they linked to the receptors. The methyl group is non-polar radicals and provided electrons to other groups 47 to create alkyl bonds The addition of a methyl group made a molecule more hydrophobic that supporting linkage with biological molecules 48 . These hydrophobic interactions were reported to contribute to the binding of many ligand-protein systems before 49 . Alkyl bonds were also reported to increase the lipophilicity of the drug and created favourable conditions for the drug to penetrate the cell membranes 50 . 275

[Find the meaning and references behind the names: Stage, Davies, Williams, Resources, Browne, Work, Elliott, Mod, Vary, Ring, Palmieri, Clin, Bignell, Caruso, Siegel, Stephens, Bray, Sameer, Pompili, Torre, Hand, Iii, Lack, Fit, Leonetti, Grant, Porru, Jemal]

Int. J. Pharmacol., 18 (2): 262-278, 2022 On the other hand, the presence of functional groups as -OH and -CO in the structure of three ligands rosmarinic acid, carnosic acid and " -bisabolol also supported protein binding The Carbonyl group at the C-ring of flavonoid played an important role in the ligand-target interaction, by hydrogen bond interaction to Ser 530 A and Arg 120 A residue 51 . In contrast with (-Me), hydroxyl and carbonyl groups are polar radicals 52 due to the high electronegativity of oxygen. Hence the hydrogen bonds (electrostatic bond between hydrogen and the more electronegative atoms) of these compounds with hydrogen atoms in the environment were created. The free energy for hydrogen bonding can vary between -1.5 and -4.7 kcal mol G 1 . The best ligand in this study, rosmarinic acid, created four hydrogen bonds with 4 TQ 9, followed by carnosic acid with three hydrogen binding toward 1 JPW. The interaction between the -OH group of " -bisabolol and the amino acid THR A:529 of 5 HID, which was not created in rigid docking, contributed to the increase of linking affinity (from -8.2 and-9.3 kcal mol G 1 ) during flexible docking Hydrogen bonds were intermolecular interactions that were common in biological complexes 53 and were contributions to the specificity of molecular recognition 54 From the better results of flexible docking, it has been shown that flexible docking provides more sites of molecular interaction than rigid docking. Otherwise, proteins can change their initial stable structure to fit with the ligands. In living organisms, proteins are flexible objects. However, rigid docking assumed that proteins and ligands were immobilized objects, so the docking was performed only at one coordinate. Therefore, the results were extremely limited. On the other hand, flexible docking tried to simulate receptors and ligands as flexible objects. Hence, the docking was performed at several coordinates 55 in which the most durable combination with the least energy required was created. In the flexible docking, a flexible amino acid inside the receptor was required as a flexible factor to be included in the running setup. Hence the ligand could adjust to the most stable protein binding site and the simulation was more reliable and just similar to what happens in vivo process CONCLUSION The ligand-protein docking is to simulate how the ligand competes with substrates inactive regions of carcinogenic proteins for inactivating that protein, leading to the inhibition of the tumour growing. Using molecular docking and pharmacophore analysis, our study has confirmed therapeutic effects and clarified the tumour-inhibition ability of Rosmarinus officinalis L. based on molecular interactions between examined compounds with the carcinogenic proteins. Five compounds i.e., rosmarinic acid, carnosic acid, (E,E)-5,9,13-pentadecatrien-2-one, 6,10,14-trimethyl, " -amorphene and " -bis-abolol from rosemary were proposed as potential compounds in colorectal tumour inhibition. The study strongly confirmed the role and the reliability of computer works in supporting other drug development studies SIGNIFICANCE STATEMENT This study discovers the ability of compounds from the herbal plant Rosmarinus officinalis L. that can be beneficial for developing drugs targeting inhibition of different proteins causing colorectal cancer. This study will help the researcher to uncover the critical areas of drug-based docking and interaction models of potential compounds of Rosmarinus officinalis L. with different target proteins that many researchers were not able to explore and at the same time emphasize the useful role of the docking method in process of drug development ACKNOWLEDGMENTS This work is supported by Nguyen Tat Thanh University under Grant No. 2021.01.54/H o -KHCN. We are also grateful to the Computational Biology Center of International University, Vietnam National University for providing the computer resources REFERENCES 1 Sameer, A.S., 2013. Colorectal cancer: Molecular mutations and polymorphisms. Frontiers Oncol., Vol. 3. 10.3389/fonc.2013.00114 2 Bray, F., J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre and A. Jemal, 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J. Clin., 68: 394-424 3 Williams, D.S., D. Mouradov, C. Browne, M. Palmieri and M.J. Elliott et al ., 2020. Overexpression of TP 53 protein is associated with the lack of adjuvant chemotherapy benefit in patients with stage III colorectal cancer. Mod. Pathol., 33: 483-495 4 Porru, M., L. Pompili, C. Caruso, A. Biroccio and C. Leonetti, 2018. Targeting KRAS in metastatic colorectal cancer: Current strategies and emerging opportunities. J. Exp. Clin. Cancer Res., Vol. 37. 10.1186/s 13046-018-0719-1 5 Davies, H., G.R. Bignell, C. Cox, P. Stephens and S. Edkins et al ., 2002. Mutations of the BRAF gene in human cancer. Nature, 417: 949-954 276

[Find the meaning and references behind the names: Zhang, Foods, Lee, Ali, Shukla, Santos, George, Hutchison, Kalra, Khan, Song, Bhargava, Kelly, Babel, Singh, Strasser, Silva, Yuan, Eck, Soc, Ferreira, Moliner, Foster, Olson, Vinod, Liebl, Spring, Faustino, Rijo, Morris, Sci, Duarte, Manandhar, Chem, Fast, Langa, Trott, Hunter, Cheung, Lippert, Jain, Banfi, Posner, Avanzi, Tools, Speed, Behrens, Novel, Morley, Kang, Future, Flora, Wong, Deep, Feinstein, Raf, Sass, Garcia, Rep, Ther, Barros, Lindstrom, Reis, Eldar, Rozenberg, Carrasco, Dias, Yin, Reddy, Webb, Lett, Pan, Cold, Thomson, Dev, Hofmann, Med, Flowers, Andrade, Yousef, Huey, Aubrey, Tang, Poy, Sandhya, Nat, Shannon, Pathak, Banji, Begum, Pfeffer, James, Small, Boyle, Springer, Look, Magnaghi, Xue, Whalen]

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[Find the meaning and references behind the names: Top, Estrela, Jorgensen, Royal, Pharm, Press, Uni, Mack, Leung, Asensi, Zainab, Mirica, Uzairu, Eds, Hanson, Schaeffer, Rizwana, King, Hajduk, Moreno, Widodo, Jaganath, Pages, Berlin, Rives, Arthur, Lab, Alwahibi, Ayaz, Ilie, Huang, Crozier, Ward, Aldous, Bio, Price, Oral, Oliva, Nmr, Smith, Wall, Jankovic, Vaca, Zheng, Boron, Snyder, Puricelli, Mena, Prod, Progress, Rotella, Zhou, Taylor, Bai, Tirado, Carlini, Ortega, Ballatore, Chen, Phillips, Clifford, Saud, Bures, Truong]

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